Highlights from Recent Cancer Literature
Journal: Cancer Research (2013)

Bhutia SK, Das SK, Azab B, Menezes ME, Dent P, Wang XY, et al. Targeting breast cancer-initiating/stem cells with melanoma differentiation-associated gene-7/interleukin-24. Int J Cancer 2013 May 30. [Epub ahead of print].Developing effective therapeutics against breast cancer initiating stem cells (CSC) represents an important objective with potential to provide an effective means for long-term management of breast cancer. Bhutia and colleagues have examined the therapeutic efficacy in breast CSCs of melanoma differentiation associated gene–7/interleukin-24 (MDA-7/IL-24), a multifunctional cancer-specific apoptosis-inducing member of the IL-10 gene family. MDA-7/IL-24 has shown profound activity against a broad spectrum of cancers in vitro, in vivo in animal models, and in a phase I clinical trial in patients with advanced cancers. The authors provide evidence that MDA-7/IL-24 is a highly potent antitumor agent in human breast CSCs (CD24−/low/CD44+). Adenovirus-mediated delivery of MDA-7/IL-24 not only restricted the proliferation of multiple human cell line–derived breast CSCs but also induced endoplasmic reticulum stress and apoptosis in vitro without affecting normal breast stem cells. Interestingly, MDA-7/IL-24 delivery diminished mammosphere formation by these CSCs and reduced expression of major Wnt-signaling pathway molecules associated with the self-renewal of breast CSCs. Of note, direct intratumoral delivery of MDA-7/IL-24 inhibited the growth of primary subcutaneous xenografts generated by breast CSCs in nude mice and also inhibited growth of untreated CSC tumors in the opposite flank of animals through its potent bystander effect. These studies broaden the potential therapeutic applications of MDA-7/IL-24 by documenting its expanded activity as an anticancer agent in breast cancer through its capacity to directly inhibit breast CSCs as well as its previously reported activity in unsorted populations of breast cancer cells.Balanis N, Wendt MK, Schiemann BJ, Wang Z, Schiemann WP, Carlin CR. Epithelial-to-mesenchymal transition promotes breast cancer progression via a fibronectin-dependent Stat3 signaling pathway. J Biol Chem 2013;288:17954–67.Although the EGF receptor (EGFR) is often upregulated in breast cancer, targeted therapies against EGFR have been ineffective in clinical trials. Balanis and colleagues show that epithelial-to-mesenchymal transition (EMT) in breast cancer is associated with an increased responsiveness to fibronectin-induced activation of STAT3 and a decreased responsiveness to EGFR-stimulated STAT3 activation. Using breast cancer cell lines, they observed that fibronectin can induce activation of STAT3 and that both EGFR and SRC are required. Upon induction of EMT via TGF-B1 stimulation, however, fibronectin-induced activation of STAT3 is enhanced, and activation of JAK2 appears to be critical. Importantly, STAT3 activation is now independent of EGFR and SRC. Thus, with EMT, the mechanism of STAT3 activation is changed in tumor cells. In a cell line derived from a metastatic breast cancer, MDA-MB-231, the authors confirm that fibronectin is a robust inducer of EGFR-independent STAT3 activation and identify the importance of focal adhesion kinases and activation of JAK2. Using three-dimensional organotypic cultures, they also suggest that fibronectin-induced STAT3 activation is important for tumor cell invasion. These data highlight the contribution of the extracellular matrix to signaling pathway activation in breast cancer. Furthermore, these findings suggest that EMT may alter fundamental mechanisms of signaling pathway activation and drug sensitivity in breast cancer.Cui SY, Huang JY, Chen YT, Song HZ, Feng B, Huang GC, et al. Let-7c governs the acquisition of chemo- or radioresistance and epithelial-to-mesenchymal transition phenotypes in docetaxel-resistant lung adenocarcinoma. Mol Cancer Res 2013;11:699–713.The majority of lung cancers are accounted for by non–small cell lung cancer, with the most common form being lung adenocarcinoma (LAD). Treatment of advanced LAD may involve sundry treatments, such as chemotherapy, radiation, targeted therapy, or a combination thereof. Despite these treatments, patient outcome remains poor often due to the generation of therapeutic resistance, in part through therapy-induced epithelial-to-mesenchymal transition (EMT). For this reason, it is critical to understand the molecular events that influence therapy resistance so as to identify novel therapeutic options. Cui and colleagues used docetaxel-resistant LAD cells with chemo/radioresistance and EMT features to demonstrate a central role for the microRNA Let-7c in regulating chemo/radioresistance and EMT phenotypes. Based on unbiased expression profiling, Let-7c was indicated to be downregulated in docetaxel-resistant cells. Importantly, enforced expression of Let-7c increased the chemo/radiosensitivity of docetaxel-resistant LAD cells, reversed EMT phenotypes, and improved survival and inhibited metastatic potential in vivo. In contrast, inhibition of Let-7c expression reduced the chemo/radiosensitivity of the parental LAD cells. Mechanistically, elevated Let-7c mitigated the expression of the apoptotic factor Bcl-xL, and that manipulation of Bcl-xL levels phenocopied the effects of altered Let-7c. Finally, expression studies revealed that Bcl-xL was increased in docetaxel-nonresponding LAD patient tissue and that its expression was inversely correlated with Let-7c expression. The results from these studies provide new mechanistic insight into how Let-7c affects the chemo/radiosensitivity of LAD cells and suggest a potential target to reestablish a therapeutic response in therapy-resistant human LAD.Tarpey PD, Behjati S, Cooke SL, Van Loo P, Wedge DC, Pillay N, et al. Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma. Nat Genet 2013 June 16. [Epub ahead of print].The malignant bone tumor chondrosarcoma is known to be driven in part by mutations in isocitrate dehydrogenase, a metabolic enzyme in which gain-of-function mutations also results in hypermethylation of DNA and histones (60% of cases). To uncover additional genetic drivers of chondrosarcoma, Tarpey and colleagues sequenced chondrosarcomas from 49 patients, identifying mutations in COL2A1 in 37%. COL2A1 encodes the alpha chain of type II collagen fibers, the major collagen constituent of articular cartilage. Although many patients had more than one mutation, consistent with loss of function, 13 patients had the same heterozygous mutation. Only a minority of patients had loss of COL2A1 expression as determined by immunohistochemistry. Thus, it remains uncertain whether these mutations represent gain or loss of function events, and how mutations in collagen may contribute to transformation. The group also identified mutations in p53 (TP53), RB (RB1), and Hedgehog signaling in 20% to 30% of tumors. These findings provide insights into the genetics of chondrosarcoma and suggest COL2A1 as a major driver mutation.Alvarez JV, Pan TC, Ruth J, Feng Y, Zhou A, Pant D, et al. Par-4 downregulation promotes breast cancer recurrence by preventing multinucleation following targeted therapy. Cancer Cell 2013 July 8. [Epub ahead of print].Very little is known about pathways that contribute to the survival and recurrence of residual breast cancer cells. Alvarez and colleagues developed conditional transgenic mouse models induced by three different oncogenic pathways [HER2 (ERBB2), MYC, and WNT1/p53+/−] that model the key features of breast cancer recurrence in women. They used these mice to analyze the properties of minimal residual disease and mechanisms of tumor recurrence with a focus on the tumor suppressor PAR-4 (PAWR), a proapoptotic protein required for cell death in multiple contexts. PAR-4 is shown to be readily detectable in primary breast tumors, and its expression is markedly downregulated in recurrent tumors that relapse following chemotherapy and oncogene downregulation. Mining of publically available gene expression data revealed that women with breast cancers expressing low levels of PAR-4 exhibited a significantly increased risk of recurrence, independent of other prognostic clinicopathologic variables. Additional mechanistic insights into the association between PAR-4 and poor prognosis in women with breast cancer came from the I-SPY 1 TRIAL, which suggested that downregulation of PAR-4 enhanced the ability of tumor cells to survive chemotherapy. Alvarez and colleagues found that residual breast cancer cells in patients treated with chemotherapy downregulated PAR-4, suggesting that chemotherapy selects for preexisting cells within the primary tumor that express low levels of PAR-4 and that these cells serve as the reservoir from which recurrent tumors arise. They subsequently used an orthotopic mouse model to determine the impact of PAR-4 knockdown on the propensity of primary HER2/neu (ERBB2)–induced breast tumors to recur and found that tumors expressing PAR-4 short hairpin RNAs regressed less often, had more metastases, and recurred more rapidly than controls, providing functional evidence that downregulation of PAR-4 promotes breast tumor recurrence locally and at distant sites. Using cellular competition assays with GFP-labeled Par-4 knockdown cells, they show that tumor cells with low Par-4 expression have a selective advantage and constitute the majority of the tumor cells within the residual lesions, suggesting that Par-4 downregulation promotes recurrence by facilitating tumor cell survival following antitumor therapy. PAR-4–dependent multinucleation of recurrent cells was identified as a mechanism of cell death following HER2/neu inhibition, representing a pathway by which oncogene-addicted cells are selected against. These data suggest that therapeutic approaches aimed at restoring PAR-4 expression in tumors that have downregulated this tumor suppressor may enhance the therapeutic response to targeted agents as well as chemotherapy.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.